Alpha-beta-substituted aliphatic acids and their salts and esters and process for their manufacture



Patented July 25, 1950 amass ALPHA-BETA-SUBSTITUTED ALIPHATIC ACIDS ANDTHEIR SALTS AND ESTERS ANDEBOCESS FOR THEIR MANUFAC- TUB Erwin Schwenk,Montclair, N. J., and Domeni Papa, Broo klyn, N. Y., assignors toSchema; Corporation, Bloomfield, N. J a corporation of New Jersey NoDrawing. Application November 20, 1945, Serial N0. 629,916

13 Claims. I

The present invention relates to the manufacture of dicyclicallysubstituted aliphatic carboxylic acids and their salts and esters.wherem one Or both of the cyclic groups are non-benzenoid, one of suchgroups, preferably, being alicyclic, the cyclic radicals being attachedto diflerent carbon atoms of the aliphatic chain, the term alicyclicbeing employed generically to cover both saturated and unsaturatedcycle-aliphatic radicals, including those having internal ringstructures, such as hexahydrobenzene, tetrahydrobenzene, tetralyl,terpene and terpene-like radicals, and cyclopentane and cyclopenteneradicals.

More particularly, our invention relates to the manufacture ofaryl-alicyclic, aryl-heterocyclic, alicyclic-heterocyclic, and otherdicyclically substituted aliphatic carboxylic acids and their salts andesters, wherein the cyclic groups are attached to different carbons ofthe aliphatic acid chain, the aliphatic acid group being preferably, butnot necessarily, acrylyl or propionyl, at least one of the cyclic groupsbeing non-benzenoid, and being either alicyclic or heterocyclic, andeither saturated or unsaturated.

The present application is a continuation in part of our copendingapplication Serial No. 544,831, filed July 13, 1944, now abandoned.

We have found that alicyclically substituted aliphatic carboxylic acids,having an olefinic double bond in activating position with reference toa methylene group in a-position to the carboxyl, such as cycloalkeneacetic acid and the cycloalkene-substituted homologous acids, andlikewise the corresponding cycloalkylidene acetic and homologous acids,having in the m-position to the carboxylic group either a methyleneradical or the group =CH-, can be condensed with a cyclic, such as anaromatic or heterocyclic aldehyde wherein the double bond of thealdehyde group forms part of a conjugated double bond system, as in thecase, for example, of benzaldehyde, cinnamaldehyde, pyridinealdehyde,furiural, quinolinealdehyde, thiophenealdehyde, etc., to form dicyclicalkene carboxylic acids, substituted on the a-carbon by the cycloalkeneradical and on another carbon by the aryl or heterocyclic group, suchproducts being useful as intermediates for synthetic reactions such asthe production of cyclopentanopolyhydrophenanthrene compounds or themanufacture of halogenated and particularly of iodinated and brominatedcompounds suitable for use as contrast agents in roentgenographicdiagnosis, as chemotherapeutic agents, and for other purposes.

, amine, with benzaldehyde,

2 According to the present invention, alicyclic carboxylic acids ofolefinic character, like A -cycloalkene acetic acid, the isomericcycloalkylidene acetic acid, and the homologous acids, having a reactivemethylene group (or a group convertible thereinto, such as in thea-POSltiOIl. to the carboxyl group, and either substituted orunsubstituted in the nucleus, are condensed in accordance with thePerkin reaction, or by various modifications of the Perkin reaction, andpreferably although not necessarily in the form of the neutralizedcompounds, like the esters and the anhydrous alkali metal salt, such asthe potassium salt, or in the form of the free acid and with the aid ofa catalyst like a tertiary amine. such as triethyl or tributylcinnamaldehyde or other aromatic aldehydes, or with a non-benzenoidcyclic aldehyde, wherein the double bond of the aldehyde group formspart of a conjugated double bond system as in cyclocitral, the nucleusof the aldehyde being substituted or unsubstituted, to form dicyclicallysubstituted alkene carboxylic acids and their salts and esters. Also,substances which may be regarded as equivalents of cyclic aldehydes maybe used, like the cyclic glyoxylic acids of the general formulaRCO.COOH, wherein R. is aryl (like phenyl) or heterocyclic (likethienyl), or other cyclic group. This reaction was quite surprising inview of the fact that the cycloalkane carboxylic acids do not take partin a Perkin type of reaction. Thus we have heated anhydrous sodium saltof cyclohexyl acetic acid with benzaldehyde in the presence of aceticanhydride and were able to isolate only cinnamic acid (produced byreaction of the henzaldehyde with acetic anhydride) but not even tracesof the expected cyclohexyl cinnamic acid.

The products may, if desired, be hydrogenated in any suitable manner toproduce the corresponding dicyclically substituted alkane carboxylicacids and their salts and esters.

The starting compounds, or only one of them, may contain substitutinggroups like hydroxyl, ether and ester groups, and halogen groups,preferably iodine. Thus 3,5-diiodo-4-hydroxy benzaldehyde,2,4,6-triiodo-5-hydroxy benzaldehyde, 3,4-diiodo benzaldehyde, 4(or2)-hydroxy-3,5,di-

brombenzaldehyde, and the corresponding derivatives of cinnamaldehydeand higher aldehydes may be employed.

.. 4 The reaction according to the invention is illus- The production ofintermediates suitable for trated by the following equations: thesynthesis of cyclopentano polyhydro phenanthrene compounds is shown bythe following:

I 5 CH0 t no n, n H H: OCH (50011 $0011 -coon (in-coon 6 O HlOOOH nooniooocinl c=o 4 Steps 1' r mono R.cn=o coon 01130- J; 1.Dccarboxylation 3. 0 'dat In the 00cm 2. N's-Hg reduction 4. Ring ciure; H180; course 0! R==cyclic residue) reaction l Halogenated compoundssuitable for the manucrncoocum err-0000,11. facture of, or use as,contrast agents for roentgenography or as chemotherapeutic agents may,in accordance with the invention, be prepared and/or R-cno 1:011:30 inthe following manner:

0001B CH0 The ester group can be saponifled to yield the free acid.

)1 111.0003 H0 A OH OH Ho cmcoomm n I N H: N 2'...

n=o Ila-CHO H H; J: 5

con -C00.CHl 111300.051. OOH

However, the halogen may be contained in one of the starting compoundsas is shown by the following:

on I one I I I I O HO CHaCOOJISE no 13;.00011 11:06 0iHi.0oc.cHcHr-l J LOOH By the careful hydrogenation of a-cyclohexenyl 3,5-diiodo 4-hydroxycinnamic acid, it is possible to obtain the corresponding saturateddiiodo acid, as described above. The iodinated compounds of theinvention are I indicated for use also as bactericidal agents and 011055 certain of them have shown effectiveness in the treatment of tropicaldiseases. Thus a-(CyC10- hexyl) -fl- (3,5-diiodo-4-hydroxyphenyl)-propion- H0 CHLOOO-CllHl in acid has proved valuable in controllingamebiasis in experimental animals. H 000 CH CE I J Analogouscondensation products can be prepared in accordance with the foregoingprinciples from terpene and terpene-like compounds. The followingreactions with menthone are representative of the application of thiscondensation procedure to this class of compounds.

5 Menthone can be converted to a carboxyllc acid as follows:

III.

0 Beiormatsky reaction dehydration gn O OH:

I. Menthone 3-isopropyl-6-meth yl A -cyclohexenyl acetic cyclohexylidencacetic acid For the Reformatsky reaction on menthone see Wallach andTholke, Ann. 323, 151 (1902).

Compounds II and III with aromatic aldehydes give compounds of thegeneral formula C CH:

a 3-iso ro yl-G-methylA clohexenyl) p p cinnamic aci d wherein Xrepresents one or more substituents in the aromatic nucleus, likehydroxyl, alkoxy, such as methoxy and ethoxy, iodo, etc.

In a similar fashion, camphor and 3,3,5-trimethyl cyclohexanone can beconverted to the corresponding alicyclically substituted cinnamic acidsand nuclearly substituted cinnamic acids.

Compound IV (X=hydrogen) on reduction gives c-(3-isopropyl 6-methylcyclohexyl) ,8- phenyl propionic acid of the following formula:

OOH

The corresponding derivatives of the higher unsaturated and (afterhydrogenation) saturated aliphatic acids, and of alkadiene carboxylicacids. may be prepared by the use of the appropriate starting compounds,as will be evident to those skilled in the art from the abovedisclosure. Where products non-iodinated in the phenyl radical butcontaining a hydroxyl group or a functional derivative thereof, areobtained, the same may be halogenated in known manner, preferably aftersaturation of the alkene chain, to produce monoor dihalo derivativessuitable for use as contrast and therapeutic agents.

The following examples illustrate specific procedures in accordance withthe invention.

EXAMPLE I d-(A -CycIOhezenyZ) cinnamic acid A mixture of 17.9 g. ofanhydrous potassium- A -cyclohexenyl acetate and 10.6 g. of benzaldehydewas heated for eight hours at 105 C. with 100 cc. of acetic anhydride.The reaction mixture was then cooled to 60 and the excess aceticanhydride cautiously decomposed with water.

3-isopropyl-6-methyl semi-solid residue extracted with ether. The acidicfraction was isolated from the ether by extraction with sodium carbonatesolution. On acidification of the sodium carbonate extracts the a- (A-cyclohexcnyl) cinnamic acid was obtained in the form of a pale yellowsolid melting at 152 C. 0n recrystallization from a mixture of acetoneand water the acid was obtained in the form of long, white, fineneedles, melting at 156-15'l C.

By the use of the isomeric anhydrous potassium cyclohexylidene acetate,this condensation yields 1 the same product. It is advisable when usingthis acid to heat the reaction mixture for a few additional hours inorder to secure a comparable yield.

The a(A -cyclohexenyl) cinnamic acid was reduced as follows: 10 g. ofthe acid were dissolved in 200 cc. of 10% sodium hydroxide. The mixturewas heated to 90 C. and, with stirring, 15 g. of Raney nickel aluminumalloy added in the course of about one hour. The mixture was stirred foran additional hour at the same temperature, then filtered by decantationfrom the nickel, and the nickel washed twice with hot water. 0nacidification of the filtrate and washings to Congo red paper withconcentrated HCl the crude ,d-phenyl-c-cyclohexyl propionic acid wasobtained in a yield of 10 g., melting at 62-65 0.

On recrystallization from a mixture of benzene and petroleum ether thereduced acid was obtained as long,'fine, white needles melting at IO-71C.

- EXAMPLEII u-(a -C'yclohexenull p-hydroxy cinnamic acid Using eitheranhydrous potassium-A -cyclohexenyl acetate or anhydrous potassiumcyclohexylidene acetate with p-hydroxy benzaldehyde under the conditionsas described in Example I, the a- (a -cyclohexenyl) p-hydroxy cinnamicacid is obtained after recrystallization from acetone and water as long,white needles melting at 194- When a- (A -cyclohexenyl) p-hydroxycinnamic acid was reduced as described in Example I, a quantitativeyield 01' ,9-(p-hydroxy phenyl) -u-cyclohexyl propionic acid wasobtained. Recrystallized from a mixture of acetone and water thesubstituted propionic acid was obtained as fine, white needles meltingat 180-181 C.

EXAMPLE III a- (M-Cyclopentenyl) p-hydrozcy cinnamic acid Following thegeneral procedure described for Example I, this acid is obtained bycondensing either potassium cyclopentenyl or potassium cyclopentylideneacetate with p-hydroxy benzaldehyde. The product is obtained in the formof white needles which melt at 183 C. with decomposition.

The (A -cyclopentenyl) p-hydroxy cinnamic acid when reduced as describedin Example I yields the a-cyclopentane-B-(p-hydroxy phenyl) propionicacid which melts at -178" 0. Recrystallized from acetone and water theproduct was obtained as white needles melting at EXAMPLE IVc-(c-fi-mcthomy-iiA dihydro naphthalene) p-hydroxy cinnamic acid Usingthe general procedure described in Example I, 12.8 g. of anhydrouspotassium-fi-meth- The reaction mixture was poured on ice and the 76oxy-l-tetralidene acetate, 6.1 g. of p-hydroxy benzaldehyde and 100 cc.of acetic anhydride were heated for to 12 hours at 105-110 C. Thecondensation product was isolated by the ether sodium carbonateextraction method, and after several recrystallizations from benzene andpetroleum ether it melted at 189-191 C. with decomposition.

Five grams of the above substituted cinnamic acid, when reduced withRaneys alloy and aqueous alkali, yielded the c-(6 methoxytetralyl-1)-p-(p-hydroxy-phenyl) propionic acid, which melted at 168-174".Recrystallization from aqueous alcohol gave the acid in the form offine, white needles melting at 182-183".

EXADLPLE V The synthesis as outlined in Examples I to N can be modifiedto avoid the use of the anhydrous alkali salts. This modification usesthe free acid, cyclohexenyl, cyclopentenyl, and other alicyclic aceticacids with the appropriate aromatic aldehyde together with suitablecatalysts, i. e.; triethyl amine, anhydrous sodium or potassium acetate,anhydrous potassium carbonate, etc.

28 g. (0.2 m.) of cyclohexenyl acetic acid, 21.2 g. (0.2 m.) ofbenzaldehyde, 20.2 g. (0.2 m.) of triethyl amine and 61.2 g. (0.6 m.) ofacetic anhydride were heated for 10-12 hours at 100-120" C. The reactionmixture was worked up as described for Example I yieldingMM-cyclohexenyl) cinnamic acid, M. P. 156157 C.

Substitution of the cyclohexenyl acetic acid by cyclohexylidene aceticacid gave a comparable yield, but required a few additional hours ofheating. Substitution of the triethyl amine by anhydrous potassiumacetate likewise gave a good yield in the condensation.

In place of cyclohexenyl acetic acid or of cyclohexylidene acetic acid,and the similarly substituted homologous acids, there may be employedacetic acid and its homologues substituted by cyclohexanol, wherein boththe hydroxyl and the acid group are joined to the same nuclear carbon.During the course of the reaction of such a cyclohexanol acetic acid orits ester with an aromatic or heterocyclic aldehyde in the presence ofacetic anhydride (or other saturated aliphatic acid anhydride), and of acatalyst like trimethylamine, dehydration of the cyclohexanol aceticacid or ester takes place with the formation of either or both of zi-cyclohexenyl acetic acid and cyclohexylidene acetic acid, or homologousacids or esters.

EXAIWPLE VI a-(A -Cyclohc:cenyl) p-hydrowycinnamic acid Ninety-threegrams (0.5 m.) of ethylcyclohexanol-l acetate, 61 gm. (0.5 m.) ofp-hydroxybenzaldehyde, 150 gm. (1.5 m.) of triethylamine and 300 cc. ofacetic anhydride were heated, preferably with stirring, for 25-35 hoursat 100-110 C. At the end of the heating period the reaction mixture wascooled to 60 and the excess acetic anhydride cautiously decomposed bythe addition of water. The resulting solution was poured into ice andthe product extracted with ether. The ether solution was washed free ofacetic acid, the ether evaporated, and the resulting residue, which wasprincipally the ester of the condensation product, was saponifled witheither aqueous or alcoholic alkali. The saponified solution was thentreated with carbon dioxide in order to convert the alkali tobicarbonate. After this treatment the solution was heated, treated withcharcoal, and filtered. Upon acidification the c-(A 8 cyclohexenyl)p-hydroxyclnnamic acid was precipitated and filtered. The productobtained melted at 191-193 C. after recrystallization from a mixture ofacetone and water.

In place of the triethylamine, other organic amines may be used forcatalyzing the condensation, as well asmetallic salts such as sodium andpotassium acetate.

a- (Cyclohexyl) -p- (p-hydroxyphenyl) propionic acid was obtained froma- (a -cyclohexenyl) -phydroxycinnamic acid by reducing 10 grams of thelatter with Raneys alloy and aqueous alkali. as described in the Journalof Organic Chemistry. 9, 175 (1944) The substituted propionic acid wasisolated in the usual manner and after recrystallligitign from aqueousacetone melted at 180- EXAMPLE v11 c-(N-Cyclohexenyl) fi-(a-juryl)acrylic acid 9.6 grams (0.1 m.) of freshly distilled furfural, 18.6, gm.(0.1 In.) of ethylcyclohexanol-l acetate, 30.2 gm. of triethylamine andcc. of acetic anhydride were heated in an atmosphere of nitrogen for20-30 hours at -110 C. The reaction product was then worked up asdescribed in Example VI and the a-(d -cyclohexenyl) fl-(c-furyl) acrylicacid was obtained in the form of a light tan substance melting at150-151.8 C. After recrystallization from a mixture of acetone and waterthe substituted acrylic acid melted at 151.3-151.8 C. a

In a similar fashion thiophene aldehyde may be condensed withethylcyclohexanol-l acetate to give the a-(d -cyclohexenyl) ,9-(c-thienyl) acrylic acid. It has been found possible to use in place ofthiophene aldehyde thiophene glyoxylic acid which is easily accessiblefrom thiophene and ethyl oxalyl chloride via the Friedel-Craftsreaction.

The n-(d -cyclohexenyl)-fi-(c-furyl) acrylic acid on reduction can beconverted to the following products:

(a) a-(Cyclohexyl)-fi-(tetrahydrofuryl) propionic acid was isolated fromthe ether extracts of the reduction product (this reduction was run withRaneys alloy and aqueous alkali, as described in Example VI) byextraction with sodium bicarbonate. The substance boiled at 174 C./2 mm.and showed n =l.4950. The ethyl ester of this acid boiled at C./2 mm.and showed n= =1.4792.

(b) From the above ether solution there was obtained the a-(CYClOhBXYl)-'y-n-propylbutyrolactone which boiled at C./3 mm. and showed n =1.4795.

EXAMPLE V'III a-(A -C'ycZohexen1 Z) fl-(3-pyridyl) acrylic acid 10.7grams (0.1 m.) of freshly distilled pyridine- 3 aldehyde, 18.6 gm. ofethylcyclohexanol-l acetate (0.1 m.), 30.2 gm. of triethylamine, and 75cc. of acetic anhydride were heated in a nitrogen atmosphere for 20-30hours at 100-110 C. The reaction mixture, after decomposing the excess 1acetic anhydride with water, was poured on ice yellow powder melting at147-152 C. After two recrystallizations from a mixture of methanol andwater the substituted pyridine acrylic acid was obtained in the form ofpale yellow needles melting at 159.5-160" C.

In a similar fashion, 2-quinoline aldehyde undergoes condensation withethylcyclohexanol-l acetate to give a-(s -cyclohexenyl) B-(quinolyl- 3-)-acrylic acid.

The product of Example VIII was converted into a-(A -cyclohexenyl)-fl-(3-pyridyl) propionic acid by Raney nickel catalyst reduction inalcohol solution at 500 pounds pressure and a temperature of 100 C. Thereduction product, after removal of the catalyst, was diluted withwater, the alcohol evaporated, and the residue recrystallized from amixture of alcohol and water. The melting point of the pure acid was129- 130 C.

Although in the foregoing the ethyl esters were generally preferredbecause of their ease of formation and relative non-toxicity of ethylalcohol, it will be evident that other esters may be employed, like thebenzyl, and especially the other lower aliphatic esters like the methyl,propyl and butyi.

EXAMPLE IX Preparation of a-(3,3,5-trimethylcyclohea:yl)-p3-(p-hydroxyphenyl) propionic acid By the usual Reformatsky reactionbetween trimethylcyclohexanone, ethylbromacetate, zinc, and a mixture ofbenzene and toluene as solvent, there is obtained the ethyl3,3,5-trimethylcyclohexanol-l acetate which boils at 103-104 C./2 mm.Many variations may be made in this procedure; for example, choice ofsolvents, type of zinc, etc. We have found that by using granular zincin a 50-50 mixture of benzene and toluene, good yields of the ethyltrimethylcyclohexanol acetate are obtained.

Saponification of the above ethyl acetate compound with alcoholic sodiumhydroxide yields the 3,3,5-trimethylcyclohexanol-1 acetic acid, which,after recrystallization from petroleum ether, melts at 116-117 C.

When the ethyl acetate derivative described above is dehydrated by anyof the usual agents, for example, anhydrous HCl, fused potassiumbisulfate, etc., there is obtained the unsaturated compound, ethyl3,3,5-trimethylcyclohexylidene acetate or the ethyl 3,3,5-trimethyl-A-cyclohexenyl acetate. The type of dehydrating agent used will determinewhich one of these two isomers is secured. The unsaturated compoundsboiled at 76 C./1 mm. When these compounds are saponified with alcoholicsodium hydroxide, there is obtained the 3,3,5-trimethylcyclohexylideneacetic acid or the isomeric A -3,3,5-trimethylcyclohexenyl acetic acid.One of these prodvets which we have isoated. and which probably is thehexylidene compound, melts at 30-81 C. after recrystallization frompetroleum ether.

By condensing 20 gm. of the trimethylcyclohexanol-l acetic acid with 12gm. of p-hydroxybenzaldehyde in the presence of 150 cc. of aceticanhydride with 40 cc. of triethylamine as c talyst, there is obtained,after working up the reaction mixture in the normal manner, a-(A3,3.S-trimethylcyclohexe i G-hydroxycinnamic acid. Satisfactory yieldsin this reaction were obtained when the reaction mixture described abovewas heated for a period of 25-35 hours at 100-110" C. The substitutedcinnamic acid, after 10 recrystallization from a mixture of methylalcohol and water, melted at 181-182 C.

The substituted cinnamic acid, when reduced with Raney's alloy andaqueous alkali as mentioned in a previous example, yielded the G'(3,3,5-trimethylcyclohexyl)-fi-(p-hydroxyphenyl) propionic acid. Thissubstituted propionic acid, after recrystallization from aqueousalcohol, melted at EXAMPLE X ethyl(3-methz/l-6-isoPr0m/lc1/clohexanol-I) acetate Preparation of thecorresponding acids and dicyclic condensation products.

EXAMPLE XI Preparation of a.- (cyclopentane) -fi- (3,5-dibrom-4-hydroxyphenyl) prom'onic acid The reduction product of Example III wasbrominated with the calculated amount of bromine in acetic acidsolution. On diluting with water, the brominated product separated outand melted at 135-137" C. After recrystallization from a mixture ofchloroform and petroleum ether, the pure dibrom compound melted at 135-136 C.

The above acids can be converted by the usual reactions into thecorresponding salts; for example, the alkali metal salts, such as sodiumand potassium, the alkaline earth metal salts, such as those of calciumand magnesium, etc.; and the amine salts, like those of mono-, di-, andtriethyl amines, dimethylamino ethanol, etc.

We claim:

1. Process for the manufacture ofcompounds of the group consisting ofacrylic acids and their salts and esters having a cyclic group attachedto each of the aand p-carbons, comprising heating a member of the groupconsisting of ali-cyclically substituted acetic acids having a doublebond connected to the cyclic carbon which is linked to the alpha-carbon,and their metal salts and esters, with a heterocyclic aldehyde whereinthe double bond of the aldehyde group forms part of a conjugated doublebond system, to effect condensation therebetween.

2. Process for the manufacture of acrylic acids, having a cyclic groupattached to each of the aand fi-carbons comprising heating the ester ofan ali-cyclically substituted acetic acid having a double bond attachedto the nuclear carbon which is linked to the a-carbon, with aheterocyclic aldehyde wherein the double bond of the aldehyde groupforms part of a conjugated double bond system to effect condensationtherebetween, and saponifying the ester so formed.

3. Process according to claim 1, wherein the alicyclically substitutedaliphatic acid compound is a cyclohexanol acetic acid ester.

4. Process according to claim 1, wherein the alicyclically substitutedaliphatic acid compound is a cycloalkanol acetic acid ester.

5. Process according to claim 1, wherein the heterocyclic radical ispyridyl.

6. A member of the group consisting of acrylic and propionic acids ofthe formula R-X-Jv OOH and their non-toxic salts and esters, wherein Ris selected from the group consisting of cycloaliphatic groups having 5to 6 carbon atoms in the ring and their lower alkyl and lower alkoxysubstitution products, R is a heteromonocyclic radical 01 the groupconsisting of iuryl, tetrahydrofury], pyridyl and thienyl radicals, andX is a two-carbon atom aliphatic chain, the carboxyl and R group beingattached to one of the carbons of X while B is attached to the othercarbon of X.

'7. Compounds as defined in claim 6 wherein R contains 6 carbon atoms.

8. Compounds as defined in claim 6 wherein 20 R is pyridyl.

9. Compounds as defined in claim 6 wherein R is thienyl.

10. Compounds as defined in claim 6 wherein R is furyl.

11. Process according to claim 1, wherein the heterocyclic radical isfury].

12 12. Process according to claim 1, wherein the heterocyclic radical isthienyl.

13. a-(A -cyclohexenyl) -fi-Pyridine 3-acrylic I acid.

ERWIN SCHWENK. DOMENICK PAPA.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,345,384 Dohrn et al Mar. 28,1944 2,400,433 'Natelson et al. May 14, 1946 OTHER REFERENCES

1. PROCESS FOR THE MANUFACTURE OF COMPOUNDS OF THE GROUP CONSISTING OFACRYLIC ACIDS AND THEIR SALTS AND ESTERS HAVING A CYCLIC GROUP ATTACHEDTO EACH OF THE A- AND B-CARBONS, COMPRISING HEATING A MEMBER OF THEGROUP CONSISTING OF ALI-CYCLICALLY SUBSTITUTED ACETIC ACIDS HAVING ADOUBLE BOND CONNECTED TO THE CYCLIC CARBON WHICH IS LINKED TO THEALPHA-CARBON, AND THEIR METAL SALTS AND ESTERS, WITH A HETEROCYCLICALDEHYDE WHEREIN THE DOUBLE BOND OF THE ALDEHYDE GROUP FORMS PART OF ACONJUGATED DOUBLE BOND SYSTEM, TO EFFECT CONDENSATION THEREBETWEEN.
 6. AMEMBER OF THE GROUP CONSISTING OF ACRYLIC AND PROPIONIC ACIDS OF THEFORMULA